Abstract 790: A high-throughput chemical screen identifies synergistic activity between neurotransmitter receptor inhibitors and crizotinib in ALK-mutated neuroblastoma

Abstract

Abstract Activating mutations in the anaplastic lymphoma receptor tyrosine kinase (ALK) represent important therapeutic targets in neuroblastoma, a common childhood cancer that accounts for 15% of all pediatric oncology deaths. One of the more common mutations, ALKF1174L, is sensitive to the sole FDA-approved ALK inhibitor, crizotinib, only at high doses and mediates acquired resistance to crizotinib in ALK-rearranged cancers. To identify compounds that would synergize with crizotinib to increase cytotoxicity in neuroblastoma cells, we devised a high-throughput small molecule synergy screen using the ALKF1174L-dependent SH-SY5Y cell line to compare cell viability between screen compound alone and screen compound in combination with crizotinib. Compounds ranged from those with clinical approval and known therapeutic indications to those with only predicted bioactivity. Of ∼10,000 compounds screened, the most recurrent hits included adrenergic and dopaminergic neurotransmitter receptor inhibitors. Validation studies with a candidate dopamine receptor D2 antagonist, chlorpromazine, resulted in increased cytotoxicity when combined with crizotinib over that of either single agent alone. These studies support further pre-clinical efforts to explore the therapeutic potential of combining crizotinib with neurotransmitter receptor inhibitors in ALKF1174L-mutated neuroblastoma. Citation Format: Nathan Moore, Srunphut Pukma, Nathanael Gray, Rani George. A high-throughput chemical screen identifies synergistic activity between neurotransmitter receptor inhibitors and crizotinib in ALK-mutated neuroblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 790. doi:10.1158/1538-7445.AM2014-790